Diseases of the respiratory system such as asthma, bronchitis, cystic fibrosis, pulmonary infections with viruses or bacteria, and a number of other respiratory diseases may be treated with various therapeutic agents which are administered to the patient either systemically, i.e. by parenteral or oral administration, or by inhalation. While the concept of inhalation treatment is intriguing in that it involves the direct delivery of the active agent to the affected target site of the body, it is also challenging to achieve effective drug delivery to the lungs as this not only requires a particular aerosol quality to be generated and delivered to the patient, but often also the collaboration of the patient who may have to perform a particular breathing manoeuvre.
Various types of inhalation devices are available that are, in principle, capable of converting solid or liquid pharmaceutical formulations into inhalable aerosol, including dry powder inhalers, metered-dose inhalers and nebulisers. Nebulisers have in common that they convert a non-pressurised liquid formulation into respirable aerosolised droplets. Depending on the mechanism by which the aerosol droplets are generated, various different types of nebulisers may be distinguished, such as jet nebulisers, ultrasonic nebulisers, and vibrating-mesh nebulisers.
Some patient groups present a particular challenge for inhalation treatment. Such patients include those that have special anatomical or physiological characteristics that require particular aerosol parameters, for example small children; or patients that are not capable of performing specific manoeuvres, such as an inspiratory manoeuvre coordinated with manually triggering the release of a drug dose, as is required in the case of some metered-dose inhalers and powder inhalers. Patients with difficulties in this respect include those patients that are severely ill, that are under sedation, or suffer from a mental disability.
For some of these special patients, in particular children, it is therefore rather difficult to make an effective use of inhalation therapy, using the inhalation devices and the pharmaceutical drugs and formulations that are available today. Nevertheless, there is a pronounced need to allow such patients to benefit from inhalation therapy. For example, there are respiratory diseases which affect in particular young children such as neonates, infants and toddlers, while rarely occurring in adults or older children. An example is infection with respiratory syncytial virus (RSV), more specifically the human respiratory syncytial virus (hRSV). RSV is a recurrent cause of severe respiratory tract infections in infants and very young children. It causes annual epidemics, especially during the winter months. RSV infection may affect the upper respiratory system, which typically involves mild and transient symptoms, or constitute a severe lower respiratory tract infection (LRTIs) involving more serious symptoms such as bronchopneumonia and bronchiolitis.
With children, the challenges of effective therapeutic aerosol delivery increase with decreasing age of the child. Typically, neonates, infants and toddlers cannot yet generate the inspiratory flow required for using breath-triggered inhalation devices or powder-inhalers. At the same time, they are not able to use the mouthpiece of a nebuliser appropriately. In fact, infants up to the age of 18 months may not even be capable of any controlled oral inhalation manoeuvre.
Moreover, the airways of young children are several times smaller than those of adults, with narrow airways, high breath resistance and thus increased risk of impaction of aerosols in the upper airways. Also the tidal volume of young children is far lower than for adults and more variable, which further increases the challenges of paediatric inhalation therapy. Hence, there is a substantial need for improved therapies for paediatric patients affected with a respiratory disease. Similarly, there is a need for improved therapies for other patients with special limitations that are affected by respiratory diseases or conditions.
With respect to RSV therapy, the only approved drug product currently available in the market is Synagis®, a humanized monoclonal antibody administered by parenteral administration. With no other adequate treatment options at hand, the standard of care for infected infants is mainly supportive (e.g., fluid/feed supplementation, observation, and respiratory support as needed). Thus, there is clearly a need for an improved therapy for patients suffering from this disease, in particular paediatric patients.
WO 2010/139808 discloses immunoglobulin single variable domains directed against the fusion protein of the human respiratory syncytial virus as potential new therapies for RSV patients. For example, the document describes certain polypeptides including SEQ ID NOs: 65-85 along with some of their characteristics in vitro and in vivo. These polypeptides comprise 3 anti-hRSV immunoglobulin single variable domains that are recombinantly linked by a flexible linker. The effectiveness of the polypeptides was shown in rats. However, it is known that biological effects observed in rat studies cannot be easily extrapolated to humans, in particular not to specific human patient populations.
Moreover, formulations of these polypeptides in the form of nebuliser solutions have been described in WO 2011/098552. However, there remains a need for devices and methods to deliver such formulations effectively to patients in need thereof.
It is an object of the invention to improve the delivery of a therapeutic aerosol to a patient who cannot easily perform breathing manoeuvres required for conventional inhalation therapy, such as a paediatric patient.
It is a further object of the invention to improve the therapy of respiratory diseases, in particular respiratory infections such as RSV infections.
A further object is to overcome any of the disadvantages of the inhalation therapies of the art.
Further objects will become clear on the basis of the patent claims and the description.